Researchers say they have used induced pluripotent stem cells (iPSCs) to advance disease-in-a-dish modeling of a rare genetic disorder, ataxia telangiectasia (A-T). The UCLA scientists say their discovery shows the positive effects of drugs that may lead to effective new treatments for the neurodegenerative disease.

A-T patients begin life with neurological deficits that become devastating through progressive loss of function in the cerebellum, which leads to severe difficulty with movement and coordination. A-T patients also suffer frequent infections due to their weakened immune systems and have increased cancer risk. A-T is caused by lost function in a gene, ATM, which normally repairs damaged DNA in the cells and preserves normal function.

Although mouse models are commonly used to study A-T, mice with A-T do not experience the more debilitating effects that humans do. The researchers say it was therefore critical to develop a human neural cell model to understand the neurodegenerative process of A-T and create a platform for testing new treatments.

One of the study leaders, Peiyee Lee, M.D., Ph.D., and colleagues used iPSC-derived neural cells developed from skin cells of A-T patients with a specific type of genetic mutation to create a disease-in-a-dish model. The researchers were able to model the characteristics of A-T in the laboratory, such as the cell’s lack of ATM protein and inability to repair DNA damage.

The model also allowed the researchers to identify potential new therapeutic drugs, called small molecule read-through (SMRT) compounds, that increase ATM protein activity and improve the model cells’ ability to repair damaged DNA.

“A-T patients with no ATM activity have severe disease but patients with some ATM activity do much better. This makes our discovery promising, because even a small increase in the ATM activity induced by the SMRT drug can potentially translate to positive effects for patients, slowing disease progression and hopefully improving their quality of life,” says Dr. Lee.

These studies suggest that SMRT compounds may have positive effects on all other cell types in the body, potentially improving A-T patients’ immune function and decreasing their cancer susceptibility. Additionally, the patient-specific iPSC-derived neural cells in this study combined with the SMRT compounds may increase scientists’ understanding of the development and progression of A-T. This iPSC-neural cell A-T disease model also can be a platform to identify more potent SMRT drugs, notes Dr. Lee. The researchers speculate that the SMRT drugs identified using this model can potentially be applied to most other genetic diseases with the same types of mutation.